ABSTRACT Dysfunctional inflammatory and wound healing responses are clinically important complications of diabetes, however the mechanisms underlying these defects remain elusive. Macrophages are cells of the innate immune system that orchestrate inflammatory and reparative responses. Evidence is emerging that macrophage dysfunction in diabetes contributes to inflammatory complications of this disease, including poor healing of skin wounds. While the mechanisms of macrophage dysfunction in diabetes are not well understood, it has recently become apparent that excess release of the cytokine IL- 1? promotes adverse wound healing. IL-1? release is regulated by the inflammasome, a pro- inflammatory complex that cleaves and activates IL-1?. In diabetes, elevated levels of circulating lipids promote macrophage lysosome damage and inflammasome activation; yet, the mechanistic links between macrophage lipid handling and IL-1? release are unclear. At sites of inflammation, macrophages undergo a shift in cellular metabolism towards fatty acid and mitochondrial oxidation pathways, a process regulated in part by the nuclear receptor transcription factor PPAR?. We hypothesize that when this metabolic shift occurs in the setting of excess lipid, macrophage lysosome damage and inflammasome activation will be enhanced. The main objective of this proposal is to determine how macrophage fatty acid metabolism contributes to inflammasome activation and poor wound healing in diabetics and to leverage this knowledge for translational investigation. Our preliminary studies demonstrate that PPAR? deficient macrophages have reduced rates of mitochondrial fatty acid utilization and less IL-1? release in response to lipid-inflammatory stress. In Aim 1, the mechanistic link between nutrient excess, mitochondrial lipid handling, and inflammasome activation will be dissected in primary macrophages in vitro. Genetic and pharmacologic approaches in combination with metabolic phenotyping, metabolomics analyses, and cell function assays will be employed. Aim 2 will then assess diabetic skin wound healing in two genetic models of macrophage fatty acid oxidation deficiency to address the in vivo links between macrophage lipid stress, inflammasome activation, and poor wound healing. In Aim 3, the effects of pharmacologic modulators of lipid metabolism on diabetic wound healing and inflammasome activation will be investigated. The results of these studies will be an important first step in the long-term goal of this research program, which is to dissect the mechanisms by which nutrient stress can impair macrophage inflammatory and reparative function in metabolic disease. The proposed studies aim to elucidate novel molecular targets that alter the crosstalk between fatty acids, mitochondrial oxidation and the inflammasome. This work is likely to have a strong positive impact on the field through identification of new pathways relevant to the treatment of diabetic wound healing complications.